This invention relates to an altered major histocompatibility complex (MHC) determinant and to the altered MHC determinant in association with an antigen. This invention also relates to the use of the altered MHC determinant in diagnostic applications and for treating or immunizing a mammal.
The major histocompatibility complex is a series of genes that code for protein molecules responsible for cell-cell recognition and interaction. The MHC of mammalian species contains three groups of genes: class I, class II, and class III. Class I and class II genes code for cell surface recognition molecules. Class III genes code for certain complement components.
The ability of cells to recognize other cells as self or as originating from another genetically different individual (non-self) is an important property in maintaining the integrity of tissue and organ structure. Class I and class II MHC products control recognition of self and non-self. The major histocompatibility system thus prevents an individual from being invaded by cells from another individual. For example, transplants from one individual generally cannot survive in another individual because of histocompatibility differences.
Histocompatibility similarities are required for cellular cooperation in induction of the immune response, and they provide a mechanism to ensure that T cells and B cells of a given individual can recognize each other for cooperation, yet recognize foreign structures at the same time. For instance, T lymphocytes, when presented with an antigen in the proper manner, react in one of two ways: through the generation of T cytotoxic lymphocytes (T.sub.c) or through amplification by T helper cells (T.sub.h) or suppression by T suppressor cells (T.sub.s) of the effects of other T or B cells. In general, T lymphocytes only recognize the antigen and respond to it when it is presented on the surface of antigen-presenting cell. This antigen-presenting cell may vary according to the type of T lymphocyte involved. Thus, in the generation of cytotoxic responses, lymphocytes and possibly macrophages present the antigen to the T.sub.c cells, while in the other types of T response the presenting cell may be a macrophage and perhaps dendritic cells.
T cells need to recognize two structures, a foreign antigen and an MHC gene product, for their subsequent activation. The process of generating T.sub.c cells and a cytotoxic response requires that the antigen be presented to the T cells in association with an MHC class I gene product. On the other hand, for B cells to be activated, binding to the antigen is necessary, plus a second signal usually given by a T.sub.h lymphocyte. However, the T.sub.h lymphocytes require the presentation of the antigen in a processed form by an antigen-presenting cell in the context of an MHC class II determinant.
In the case of B cell activation, it has been established that whatever the antigen-presenting cell is, it must process the antigen before presenting it to the T.sub.h lymphocytes. This involves taking up the antigen, sequestering it in intracellular compartments, and re-expressing the antigen or a portion thereof on the surface of the antigen-presenting cell in association with a class II MHC determinant. The T.sub.h cell must be able to recognize the processed antigen and class II markers on both the antigen-presenting cell and the B cell. When each of these requirements is fulfilled, the B cell will be stimulated to proliferate, which greatly increases the number of cells capable of synthesizing specific antibody. These then differentiate into plasma cells, which secrete large amounts of antibody. A similar response employing class II receptors on T.sub.s suppressor cells and class II MHC markers on macrophages and B cells may be operative in induction of T suppressor activity, which turns off antibody production.
Much remains to be understood of the interactions between antigens and MHC class I and class II molecules, and of the way in which T cell receptors recognize MHC-antigen complexes. For instance, a large proportion of MHC molecules is likely to be occupied by a variety of preexisting (probably endogenous) peptides. This obscures the interpretation of peptide-binding assays and hampers crystallographic studies of peptide-MHC complexes. It would be extremely useful to be able to isolate peptide-free MHC molecules, which could be loaded by a single type of peptide.
In addition, there exists a need in the art for knowledge of the peptide motifs of individual MHC alleles to aid in making T-cell epitope predictions, to aid in synthetic or recombinant vaccine development, and for intervention in autoimmune diseases or graft rejection.